In recent years there has been intensive investigations to further the cause of asymmetric reduction specifically as it relates to the development of new pharmaceutical intermediates and bulk drugs. This effort has been spurred by the benefits of single isomer or enantiopure compounds used as pharmaceutical drug agents. Factors such as availability and the overall economics and safety related to the use of new reagents has promoted the idea that an ideal chiral reducing agent could be fabricated from cost effective precursors with the chiral moiety being derived from readily available members of the chiral pool.
Among the techniques for introducing chirality that are available to the industrial chemist, the one that has proven especially useful is asymmetric reduction.
Reduction of unsymmetrical ketones to alcohols is among the most useful. This reaction is achieved by the overall addition of hydride ("H--") to one face of the carbonyl group leading preferentially to the formation of one enantiomer.
In 1992, von dem Bussche-Hunnefeld, Beck, Lengweiler, and Seebach published an article in Helvetica Chimica Acta, vol. 75, 438-441 regarding the use of so-called TADDOLs (see page 75 for the list of abbreviations) as chiral shift reagents in NMR spectroscopy. Although they discussed the formation of host-guest complexes between a few TADDOLs and alcohols, the focus of this article was on the utility of certain TADDOL compounds in NMR spectroscopy.
More recently, a paper by Seebach et al. in Croatica Chemica Acta, vol. 69, no. 2, 1996, pages 459-484, discussed a method that allows reduction of asymmetric ketones to secondary alcohols and then taking advantage of the guest-host complex formed between the metal hydride complex and the alcohol produced to achieve enantiomeric enrichment. The work described in that paper was based mainly on Noyori et al.'s results (J. Am. Chem. Soc. vol. 106, 1984, pages 6717-6725; J. Am. Chem. Soc. vol. 106, 1984, pages 6709-6716) which suggested that high enantiomeric selectivity was achievable only with aluminum complexes bearing an additional alkoxide ligand such that there is only one hydride bound to aluminum. Seebach et al. thus restricted their experiments to the use of alkoxide-bearing aluminum hydride complexes. Seebach et al. also did not investigate the influence on the chemical and optical yields of factors such as the nature of solvent (THF was the only solvent used), starting amounts of reactants, and relative amount of solvents in a system using a solvent-mixture to name a few.
There have also been many journal articles discussing the process of host-guest complexation, but they typically involved the investigation of a very narrow class of compounds under certain conditions to achieve substantial enantiomeric excess. A number of articles published by Cram and co-workers, for instance, discuss mainly the use of crown ethers in the formation of various host-guest complexes (see for example J. Am. Soc. 1997, 99, 2564-2571). In addition, the guest compounds they discuss are typically charged species such as salts of quaternary amines.
In the J. Org. Chem. 1991, 56, 7332-7335, Toda and Tanaka describe the optical resolution of bicyclic ketone derivatives bicyclo[2.2.1]heptanone, bicyclo[2.2.2]-octanone, and bicyclo[3.2.1]octanone using the host compounds (S,S)-(-)-1,6-bis(o-chloro-phenyl)-1,6-diphenyl-2,4-diyne-1,6-diol, (R,R)-(-)-trans-4,5-bis(hydroxydiphenyl)-2,2-dimethyl-1,3-dioxacyclopentan e, and (S)-(-)-10,10'-dihydroxy-9,9'-biphenanthryl. Although this reference teaches a process of optical resolution via inclusion complexation, it is restricted to bicyclic ketone derivatives.
The preparation of optically active glycidic esters by inclusion complexation using the chiral host compound (R,R)-(-)-trans-4,5-bis-(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxacycl opentane and its derivatives was described by Toda, Takumi, and Tanaka in Tetrahedron: Asymmetry Vol. 6, No.5, 1059-1062. While the experiments they performed involved inclusion complexation, they were restricted to resolution of optically active glycidic esters. Toda and co-workers also discussed the results of experiments involving optical resolution using TADDOL type compounds in J. Chem. Soc., Chem. Commun., 1995, 639, but they confined their investigation to certain sulfoxides and sulfinates.
In J. Org. Chem. 1992, 57, 6825-833, Weber et al. discuss the optical resolution using host-guest complexation of several types of guest molecules ranging from alcohols to a few monocyclic systems. However, all of the molecules that Weber et al. used as guests are small molecules such as MeOH, EtOH, 2-PrOH, t-BuOH, and benzene which were also used as solvent at the same time. As Weber et al. states, "[t]he formation and stability of these crystalline inclusion complexes are affected by functional as well as by topological complementarity and consequently are sensitive to small structural variations." Thus, even though the process they discussed involved alcohols, they clearly suggest there is no guarantee the same process will also work for alcohols with structures larger and more complex than the ones they investigated.
It is important to note that none of the above references has undertaken a systematic investigation of the many factors that play a role in the success of asymmetric reduction process and host-guest complexation. A full understanding of the process of host-guest complexation alone has been hindered by the complexity of the molecular interactions between the host and guest that determine the probability of formation of a host-guest complex. There is also little or incomplete understanding regarding the influence of other factors--for instance, the nature of solvent, reaction temperature, molar ratio of the solvents in a solvent-mixture, and duration of the reaction--on the enantiomeric excess obtainable in an optical resolution procedure, and even whether factors such as the scale of the reaction can actually have an impact on the enantiomeric excess of a product resolved via inclusion crystallization. All of these contribute to the unpredictability of the outcome of reactions involving host-guest complexation. It is thus highly desirable to come up with a systematic investigation of various factors that come into play in host-guest complexation and also to examine in-depth the benefits that can be derived from coupling the process of host-guest complexation with another process such as asymmetric reduction.